The behavioral and biochemical effects of neuropeptides and GABA agonist muscimol were studied by comparing the acetylcholine turnover rate (TR-ACh) in the rat hippocampus and hippocampal regions with extinction of a food reinforced lever press response after intraseptal injection of such compounds. We have shown that muscimol decreases the hippocampal TR-ACh and increases extinction responding in a dose-dependent manner. Intraseptal beta-endorphin, which decreases the hippocampal TR-ACh through an activation of septal GABAergic interneurons, also increases extinction responding. On the other hand, intraseptal substance P, which decreases the hippocampal TR-Ach in a manner unrelated to septal GABAergic mechanisms, fails to increase extinction responding. The TR-ACh in various hippocampal regions after intraseptal injection of muscimol and substance P was also studied. Muscimol decreases the TR-ACh only in the ventral hippocampus, whereas substance P decreases it only in the dorsal hippocampus. We hypothesize that a lowering in the cholinergic input to the ventral hippocampus is capable of increasing extinction responding, whereas a decrease in the input to the dorsal hippocampus is without such an effect. Hence, the cholinergic projections to the two hippocampal areas are modulated by different transmitter systems and have different physiological functions. Studies were also performed to characterize the GABAergic control of the substantia inominata-cortical cholinergic pathway in the rat. It is known that activation of GABA receptors in the substantia inominata by microinjection of muscimol decreases the TR-ACh in the cortex. To test the hypothesis that such control may be tonic, in separate experiments bicuculline (a GABA antagonist) was injected into the substantia inominata and the major GABAergic input to the region was destroyed by lesioning the nucleus accumbens with kainic acid. Neither treatment altered the TR-ACh in the cortex. This indicates that the GABAergic control of this cholinergic projection is similar to that in the septal-hippocampal pathway, which also lacks a tonic GABAergic control.